There has been considerable interest in the development of dopamine D3 receptor (DRD3) partial agonists and antagonists for the treatment of substance use disorders. Pre-clinical evidence overwhelmingly supports the use of these drugs, but translation to humans has remained elusive due to the lack of selective compounds that are suitable for use in humans. Although it has been established for full antagonists, little in vivo occupancy data are available with DRD3 partial agonists. Here we investigate for the first time in healthy controls, the in vivo occupancy of a novel D3 partial agonist (BP1.4979) at the DRD3 and DRD2. Participants received either a single dose (1, 3, 10 or 30 mg) or a subchronic regimen (5-7 days, q.d. or b.i.d) of BP1.4979, with the last dose given at 1, 12 or 24 h prior to scanning with [11C]-(+)-PHNO. Single and subchronic administration of BP1.4979 dose-dependently occupied the DRD3 and DRD2, and this occupancy was preferential for the DRD3, notably at longer time points after administration of BP1.4979. Also consistent with preference for the DRD3, prolactin levels were minimally increased, and no subjective effects of BP1.4979 were reported. Serum levels of BP1.4979 were higher than its active metabolite, BP1.6239, while no notable increases in the inactive metabolite, BP1.6197, were found. These findings indicate the range of doses that can be used to occupy selectively the DRD3 over the DRD2 with BP1.4979 and speak to the use of in vivo imaging approaches in dose finding studies.

中文翻译：

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新型D3部分激动剂BP1.4979对多巴胺D2和D3受体的占用：一项针对人体的[11C]-（+）-PHNO PET研究。

对多巴胺D3受体（DRD3）部分激动剂和拮抗剂的开发已经引起了极大的兴趣，以治疗物质使用障碍。临床前证据绝大多数支持使用这些药物，但是由于缺乏适用于人类的选择性化合物，因此向人类的翻译仍然难以捉摸。尽管已经为完全拮抗剂建立了证据，但DRD3部分激动剂的体内占有率数据很少。在这里，我们首次在健康对照中研究了DRD3和DRD2处新型D3部分激动剂（BP1.4979）在体内的占有率。参与者接受单次剂量（1、3、10或30毫克）或亚慢性治疗方案（5-7天，每日或两次）BP1.4979，最后一次剂量在扫描前的1、12或24小时给予用[11C]-（+）-PHNO。BP1.4979的单次和亚慢性给药剂量依赖性地占据了DRD3和DRD2，这种占用是DRD3的优先选择，特别是在BP1.4979给药后的较长时间点。同样与对DRD3的偏爱相一致，催乳素水平几乎没有增加，也没有报道BP1.4979的主观影响。血清BP1.4979的水平高于其活性代谢物BP1.6239，而无活性代谢物BP1.6197则没有显着增加。这些发现表明可以用BP1.4979取代DRD2选择性地占据DRD3的剂量范围，并说明在剂量寻找研究中使用体内成像方法。尤其在BP1.4979给药后的较长时间点。同样与对DRD3的偏爱相一致，催乳素水平几乎没有增加，也没有报道BP1.4979的主观影响。血清BP1.4979的水平高于其活性代谢物BP1.6239，而无活性代谢物BP1.6197则没有显着增加。这些发现表明可以用BP1.4979取代DRD2选择性地占据DRD3的剂量范围，并说明在剂量寻找研究中使用体内成像方法。尤其在BP1.4979给药后的较长时间点。同样与对DRD3的偏爱相一致，催乳素水平几乎没有增加，也没有报道BP1.4979的主观影响。血清BP1.4979的水平高于其活性代谢物BP1.6239，而无活性代谢物BP1.6197则没有显着增加。这些发现表明可以用BP1.4979取代DRD2选择性地占据DRD3的剂量范围，并说明在剂量寻找研究中使用体内成像方法。被发现。这些发现表明可以用BP1.4979取代DRD2选择性地占据DRD3的剂量范围，并说明在剂量寻找研究中使用体内成像方法。被发现。这些发现表明可以用BP1.4979取代DRD2选择性地占据DRD3的剂量范围，并说明在剂量寻找研究中使用体内成像方法。